Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
  • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug

Definitions

• the present invention relates to compositions comprising synergistic combinations of polymeric components and poorly soluble drugs with enhanced solubility of the drugs.
• the invention also relates to pharmaceutical dosage forms prepared with these compositions.
• polymers include cellulose acetate phthalate (CAP), hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethylcellulose phthalate (HPMC-P), polyvinylacetate phthalate (PVAP), polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP).
• CAP cellulose acetate phthalate
• HPMC hydroxypropylmethyl cellulose
• HPMC-P hydroxypropylmethylcellulose phthalate
• PVAP polyvinylacetate phthalate
• PVA polyvinyl alcohol
• PVP polyvinylpyrrolidone
• compositions comprising two polymers and a poorly soluble drug with the drug being present predominantly, if not exclusively, in the amorphous state.
• Some preferred aspects of the invention include compositions containing a cellulosic polymer, polyvinyl acetate phthalate (PVAP) and a poorly soluble drug having a solubility at least 1.5 times greater than the equilibrium solubility of the crystalline form of the drug.
• PVAP polyvinyl acetate phthalate
• Such compositions may be prepared by dissolving the polymeric components and the drug in a common solvent system of one or more solvents and then evaporating the solvent to yield a substantially dry powder with drug primarily in the amorphous form.
• the powder includes the primarily amorphous form of the drug intimately in contact with but not covalently bound to the blend of polymers.
• a further aspect of the invention includes solvent systems containing the above mentioned poorly soluble drug, cellulosic polymer and PVAP as a dissolved mixture therein.
• the dissolved mixture of polymers and drug may be coated onto sugar spheres or other pharmaceutically acceptable substrates, which upon evaporation of the solvent system, yields a layer of polymers and substantially amorphous drug on the surface of the sugar spheres.
• the polymers employed are polyvinylacetate phthalate (PVAP) and hydroxymethylpropyl cellulose (HPMC).
• pharmaceutical dosage forms such as tablets, capsules or the like that include the solubility-enhanced drugs, prepared as stated above, e.g. as a powder or coated sphere, along with commonly used pharmaceutical excipients to prepare tablets, capsules and other orally-ingestible dosage forms that are known in the art.
• a method of enhancing the solubility of a poorly soluble amorphous drug includes dissolving a poorly soluble drug in crystalline form in a solvent system along with a mixture of two polymers, preferably the cellulosic polymer and PVAP, followed by evaporating the solvent to yield substantially dry powder containing the amorphous drug intimately in contact with but not covalently bound to the blend of polymers.
• Fig. 1 is a graph displaying the dissolution profile of the product of Example 1 and Comparative Examples A-E.
• Fig. 2 is a graph displaying the dissolution profile of the products of Examples 1-4 and Comparative Examples A-E.
• amorphous shall be understood to mean a substantially random array of molecules in the solid state - i.e. non-crystalline;
• non-sink shall be understood to mean dissolution conditions under which the concentration of a drug, in dissolved and/or undissolved form, is greater than the equilibrium solubility of the crystalline drug;
• orally-ingestible dosage form shall be understood to mean any
• pharmaceutically acceptable dosage form e.g. tablet, capsule, caplet, etc. or any other veterinary or confectionary product capable of being taken via the oral route of administration;
• the poorly soluble drugs contemplated for inclusion in the compositions and methods of the invention typically have a measured solubility of ⁇ 0.01 g/mL in water.
• the inventive solubility-enhanced compositions comprise a cellulosic polymer, polyvinyl acetate phthalate (PVAP) and a poorly soluble drug.
• the cellulosic polymer may be hydroxypropylmethyl cellulose (HPMC). Low viscosity grades of HPMC are preferred.
• HPMC having viscosities of less than about 100 centipoise as 2% (w/v) solutions in water are particularly preferred.
• Suitable commercially available HPMC products include those sold under the Methocel ® trade name with grades such as E3 being well suited for inclusion herein.
• PVAP is a reaction product of phthalic anhydride and partially hydrolyzed polyvinyl acetate. During the phthalic anhydride addition process, the free hydroxyl groups on the partially hydrolyzed polyvinyl acetate are partially esterified with phthalate groups. Thus, there are acetate, phthalate and free (unreacted) hydroxyl groups on the PVAP polymer backbone.
• the poorly soluble drug may be any drug having a solubility of ⁇ 0.01 g/mL in water.
• Poorly soluble drugs possessing functional groups capable of interacting with the functional groups on the cellulosic polymer and PVAP are preferred.
• Drug molecules possessing sufonylurea, sulfonamide, halogen, alcohol, amine, amide, phenyl, pyrazole, triazole, triazolone, dioxolane, ether, ketone, piperazine or pyrazine groups are particularly preferred.
• Glipizide, itraconazole, celecoxib and fenofibrate are particularly preferred, since they contain one or more of the functional groups mentioned above.
• the hydroxyl groups on the cellulosic polymer and PVAP can form hydrogen bonds with electronegative species on drug molecules such as oxygen or nitrogen atoms. Furthermore, the phenyl groups on PVAP can form ⁇ - ⁇ (Pi-Pi) interactions with other aromatic groups on drug molecules to further stabilize the molecular associations.
• the combination of these stabilizing interactions from both the cellulosic polymer and PVAP leads to a synergistic stabilization of the drug molecule - i.e. the polymers in combination more effectively stabilize the amorphous form of a poorly soluble drug than either polymer alone. It is appreciated that, depending on the nature of the drug molecule, the optimum ratio of cellulosic polymer to PVAP may change.
• the amount of poorly soluble drug in a composition (i.e. drug concentration) comprising the drug, cellulosic polymer and PVAP may be as high as 50% w/w.
• a poorly soluble drug concentration less than about 40% is preferred.
• powder compositions can include up to about 50-99.9%) of the polymer blend.
• a poorly soluble drug concentration less than about 30%> is particularly preferred.
• a preferred ratio of cellulosic polymer to PVAP may change depending on the nature of the poorly soluble drug. It is generally preferred that the ratio of cellulosic polymer to PVAP be greater than 1.
• the ratio of cellulosic polymer to PVAP is at least about 2: 1 while in other aspects, the ratio of cellulosic polymer to PVAP of 3: 1 is more preferred.
• Surfactants, disintegrants and hydrophilic agents may be incorporated in the compositions comprising poorly soluble drug, cellulosic polymer and PVAP to further enhance the drug solubility and/or dissolution rate.
• Suitable surfactants include sodium lauryl sulfate, poloxamers and polysorbates.
• Suitable disintegrants include native starch or partially pre-gelatinized starch such as Starch 1500®, StarCap 1500®, croscarmellose sodium, sodium stearyl fumarate, crospovidone and sodium starch glycolate.
• Suitable hydrophilic agents used to facilitate water ingress into the compositions, include polyethylene glycols, lactose, mannitol and other water-soluble sugars.
• a general method for preparing the inventive compositions is to dissolve the poorly soluble drug, cellulosic polymer and PVAP in a common solvent and then evaporate the solvent in a rotary evaporator, or other equipment designed for solvent removal such as a spray dryer, to yield an amorphous solid dispersion.
• An alternate method for preparing the inventive compositions is to coat the solution of poorly soluble drug, cellulosic polymer and PVAP in a common solvent onto sugar spheres or similar substrate, removing the solvent in the process and yielding a substantially
• Suitable solvents include dichloromethane, chloroform, methanol, ethanol, acetone, water and mixtures thereof.
• dichloromethane and methanol can be used successfully as solvents for poorly soluble drugs.
• the in vitro solubility of the drug within the inventive composition is routinely determined by placing the drug in an aqueous medium within a dissolution vessel with stirring. Samples are then taken at regular time intervals and measured using a spectrophotometer capable of measuring at the wavelength at which the drug molecule absorbs. In this way, the amount of drug dissolved versus time can be determined.
• it is important to establish non-sink conditions in the dissolution medium i.e. the concentration of a drug, in dissolved and/or undissolved form, is greater than the equilibrium solubility of the crystalline drug.
• the amount of drug dissolved from the inventive compositions can then be compared to the amount of crystalline drug dissolved to determine whether any enhancement has been attained.
• compositions comprising poorly soluble drug, cellulosic polymer and PVAP may be further processed into common orally-ingestible dosage forms.
• hard gelatin capsules may be filled with the solid dispersions or coated pellets along with excipients such as disintegrants, flow aids and surfactants.
• compositions may be further formulated with tabletting excipients such as disintegrants, flow aids, binders, surfactants and lubricants and compressed into tablets.
• tabletting excipients such as disintegrants, flow aids, binders, surfactants and lubricants and compressed into tablets.
• the tablets may also be coated with film coatings.
• Suitable disintegrants include native starch or partially pre-gelatinized starch such as Starch 1500®, or StarCap 1500® croscarmellose sodium, sodium stearyl fumarate, crospovidone and sodium starch glycolate.
• Suitable surfactants include sodium lauryl sulfate, poloxamers and polysorbates.
• Suitable lubricants include magnesium stearate and stearic acid.
• Flow aids include colloidal silicon dioxide and talc.
• the binder may be microcrystalline cellulose (MCC), lactose, calcium phosphate dehydrate (DCP), a fully or partially pre-gelatinized starch such as Starch 1500, or StarCap 1500, trademarks of Colorcon.
• MCC microcrystalline cellulose
• DCP calcium phosphate dehydrate
• Starch 1500 or StarCap 1500, trademarks of Colorcon.
• the examples below demonstrate that the blend of polymers, when evaporated with the poorly soluble drug, enhances the solubility of the drug better than when either polymer is used alone in a similar system. In many aspects, the enhancement in solubility achieved by the blend is clearly synergistic. While additional amounts of a single polymer may in theory be capable further enhancing the solubility of specific drugs, there are sometimes concerns and drawbacks associated with using excessive amounts of polymer.
• drugs having lower per milligram potency would not benefit from systems containing more than 80% of a single polymer. Such systems would cause the final dosage form to be unnecessarily bulky, potentially difficult to swallow and thus undesirable in the eyes of the consumer. Stated in another way, the amount of inventive blend needed for a therapeutic dosage would be too great to fit in a suitable oral dosage form.
• the amount of PVAP is too high relative to the other excipients in the dosage form, an enteric release or an otherwise undesirable pharmacokinetic release profile may be observed.
• Economic considerations also come into play, which dictate using minimal amounts of polymer to achieve the desired result of enhanced solubility. That is, lower amounts of polymer blends rather than higher amounts of single polymers allow the solubility of the drug to be enhanced thus reducing material costs, spray drying time, etc.
• Example 1 Solid Dispersion Comprising GZrHPMC E3:PVAP (1:3:1)
• Solid dispersions were prepared in the same manner as in Example 1 except that the ratios of glipizide :HPMC E3:PVAP were 1 :2:2 and 1 : 1 :3 for Examples 2 and 3, respectively.
• Glipizide 50 grams
• PVAP 50 grams
• HPMC E3 150 grams
• a methanol-dichloromethane (1 : 1) solvent system to give a total solute concentration of 7% (w/v).
• 1 Kg of Suglets® sugar spheres 20-25 mesh (850-7 ⁇ ) were loaded into the fluid bed processor (Glatt GPCG 2), equipped with a 4-inch Wurster column, and heated with dry air to a temperature of 35°C.
• the previously prepared solution of glipizide, PVAP and HPMC E3 was then sprayed onto the fluidized sugar spheres.
• Solid dispersions were prepared in the same manner as in Example 1 except that only one polymer was used in each case, and the ratio of single polymer to glipizide was 4: 1.
• HPMC-AS, HPMC E3 and PVAP were used as the single polymer for Comparative Examples A, B and C, respectively.
• the concentration of non-solvent ingredients in the methanol-dichloromethane solvent was again 6.2% (w/w).
• Crystalline glipizide was used without further modification.
• Dissolution was performed using a USP dissolution Apparatus II (Distek dissolution system model 2100, USA) connected to a UV-VIS spectrophotometer (Agilent, USA).
• the compositions were tested by establishing non-sink dissolution condition as follows. Each solid dispersion (2 g overall; 417 mg glipizide on a theoretical basis) was added to 500 mL of USP phosphate buffer (pH 7.5). In the case of coated sugar spheres, 12 grams were added to the dissolution vessel, which again was equivalent to 417 mg glipizide on a theoretical basis.
• the theoretical concentration of glipizide in the dissolution medium was 0.834 mg/mL, which is three times the equilibrium solubility of crystalline glipizide.
• the dissolution medium was maintained at 37 ⁇ 0.5 °C, and the paddle speed was 50 rpm. Samples were
• Example 5 Solid Dispersion Comprising ITZrHPMC E3:PVAP (1:3:1)
• Example 6 Solid Dispersion Comprising Celecoxib: HPMC E3:PVAP (1:3:1)

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• 2013
  • 2013-04-30 WO PCT/US2013/038825 patent/WO2013169523A1/fr not_active Ceased

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